Gene expression analysis of Cbp deficient LSK cells

The transcriptional coactivator Cbp is critical for hematopoietic stem cell (HSC) development. However, its role in adult HSC and the mechanistic detail of Cbp control of HSC function remains unknown. Using conditional deletion of Cbp in the adult HSC compartment, we demonstrate an altered balance between differentiation and self-renewal with gradual loss of phenotypic HSC, differentiation defects in lower compartments and the development of myeloid malignancies. In addition, we demonstrate that Cbp -/- HSCs reconstitute hematopoiesis with lower efficiency than their wild type counterparts and readily exhaust over time when placed under the replicative stress of serial transplantation. Furthermore, we demonstrate abnormal cell cycle (re)entry and apoptosis in HSC which, with preferential differentiation, also contribute to stem cell exhaustion. Finally we demonstrate global transcriptional abnormalities predicted to alter cell cycle control, balanced differentiation and HSC function upon Cbp deletion and link Cbp to a critical HSC transcriptional regulatory network through genome-wide analysis of Cbp binding. Genome-wide gene expression analysis of LSK population after Cbp deletion. The LSK population of bone marrow is enriched for hematopoietic stem cells. Total RNA was extracted from flow-sorted LSK population of bone marrow, 4 weeks after pIpC induced deletion of Cbp. 2 replicates for Cbp wt control, 2 replicates for Cbp Mx.